Two general concepts form the basis for our studies on the mechanisms of carcinogenesis. First is the concept that modulation in the phosphorylation of plasma membrane proteins serves a significant role in the process of neoplastic transformation. This concept is supported by our recent studies and by studies on oncogene products, such as pp60[unreadable]src[unreadable]. Second is the concept that carcinogenesis results from defects in the integrated control of cell proliferation and differentiation. This concept is also supported by our recent studies, by studies on normal and leukemic hematopoietic cells, and by studies on cells infected with viruses that express retroviral oncogene products. Our studies focus on experiments to determine how these two processes interface in mediating carcinogenesis. We will establish if modulation in plasma membrane phosphorylation influences the integrated control of cell proliferation and differentiation in normal cells and then determine if the initiation of carcinogenesis or complete transformation results from the development of defects in this regulatory process. These studies will employ "normal" mesenchymal stem cells, clones of initiated mesenchymal stem cells and mesenchymal stem cells infected with temperature-sensitive oncogenic avian sarcoma virus. It is our hypothesis that, by determining if and how plasma membrane phosphoproteins influence the integrated control of normal and neoplastic stem cell proliferation and differentiation, we will acquire the necessary insights to design experiments to establish the mechanism by which these phosphoproteins mediate carcinogenesis. (A)